The Wistar-Kyoto (WKY) rat has been proposed as a useful animal model in which to study the connection between stress responsiveness and vulnerability to depressive behavior. Physiologically, the WKY rat shows greater susceptibility to stress-induced gastric ulcers than other strains. Endocrine studies report that WKY rats have high levels of stress-induced adrenocorticotropin and low levels of corticotropin releasing hormone, suggesting a defective feedback in the hypothalamic-pituitary-adrenal (HPA) axis. Our research has revealed significant differences in central norepinephrine (NE) and serotonin (5-HT) sites in WKY rats when compared to Sprague-Dawley rats. Treatment with desipramine (a NE uptake blocker), but not paroxetine (a 5-HT uptake blocker), decreased immobility time in the Porsolt forced swim test, and reduced ulcer incidence, implicating the NE system in the mediation of depressive behavior in WKY rats. This grant is aimed at further substantiating the value of the WKY model, and is designed to determine the mechanisms that mediate the disease condition. Differential sensitivity to antidepressants with distinct pharmacological actions may provide useful information regarding the underlying substrates that contribute to a selective response in the WKY rat. Thus the central objective is to ascertain whether antidepressants that target specific neurotransmitter sites in the brain, will alleviate depressive behavior and attenuate the animal's responsiveness to stress. This behavioral response is expected to decrease ulcer susceptibility, modify feedback in the HPA axis, and reverse the characteristic NE and 5-HT receptor alterations in the WKY rat. A positive answer to this objective will provide significant information regarding the mechanisms that underlie depressive behavior and ulcer susceptibility in this vulnerable rat strain. The information gained from this study could provide a better understanding of why a clinical response is observed in some populations of depressed patients, while a resistance in treatment response is seen in others.